Hnrnpab regulates neural cell motility through transcription of Eps8

Lampasona, Alexa A.; Czaplinski, Kevin

doi:10.1261/rna.067413.118

Cited by 10 publications

(5 citation statements)

References 100 publications

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“…For probands with HNRNPAB variants, DD/ID is common, as are delayed speech and language, ASD, hypotonia, and strabismus. Little is known about hnRNPAB outside of cancer, but it has been shown to regulate expression of neurodevelopmental genes and those involved in glutamate signaling, as well as neural cell motility [ 133 , 134 ]. Probands with HNRNPH3 -related disorder have a high prevalence of DD/ID, like the other HNRNPH disorders, although they manifest characteristic hearing loss as well.…”

Section: Discussionmentioning

confidence: 99%

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Study

2021

Genome Med

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Background With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

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Section: Discussionmentioning

confidence: 99%

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Study

2021

Genome Med

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“…Romer-Seibert et al [152] Hnrnpab Eps8 SVZ cell migration Lampasona et al [156] NSC neural stem cell, OB olfactory bulb cortical development [65]. As a second example, timed Wnt3 secretion from thalamocortical axons around midneurogenesis regulates both the composition of ribosomal proteins and the subset of mRNAs that are associated with polysomes [34].…”

Section: Rabgef2mentioning

confidence: 99%

Translating neural stem cells to neurons in the mammalian brain

2019

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The mammalian neocortex underlies our perception of sensory information, performance of motor activities, and higherorder cognition. During mammalian embryogenesis, radial glial precursor cells sequentially give rise to diverse populations of excitatory cortical neurons, followed by astrocytes and oligodendrocytes. A subpopulation of these embryonic neural precursors persists into adulthood as neural stem cells, which give rise to inhibitory interneurons and glia. Although the intrinsic mechanisms instructing the genesis of these distinct progeny have been well-studied, most work to date has focused on transcriptional, epigenetic, and cell-cycle control. Recent studies, however, have shown that posttranscriptional mechanisms also regulate the cell fate choices of transcriptionally primed neural precursors during cortical development. These mechanisms are mediated primarily by RNA-binding proteins and microRNAs that coordinately regulate mRNA translation, stability, splicing, and localization. Together, these findings point to an extensive network of posttranscriptional control and provide insight into both normal cortical development and disease. They also add another layer of complexity to brain development and raise important biological questions for future investigation. Facts • Numerous posttranscriptional regulators including RBPs and miRNAs are expressed in a temporally dynamic and cell-type specific manner during embryonic corticogenesis. • Posttranscriptional mechanisms control cell fate decisions of embryonic and adult neural precursor cells. How do RBPs and miRNAs contribute to neurodevelopmental and neurological disorders?

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“…Sinnamon et al (6) have reported that hnRNP AB may serve a key role in the maintenance, differentiation and survival of neuronal stem cells by activating glutamate signalling pathways. Lampason et al (7) demonstrated that hnRNP AB promoted the migration of normal neural cells by regulating exocrine gland-secreted peptide 8 transcription during the development of the central nervous system in mouse models. Other studies have revealed that abnormal hnRNP expression serves an important role in the occurrence and development of malignant tumours, including lung cancer (8), hepatocellular carcinoma (9) and CRC (10).…”

Section: Introductionmentioning

confidence: 99%

High hnRNP AB expression is associated with poor prognosis in patients with colorectal cancer

et al. 2019

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Heterogeneous ribonucleoprotein AB (hnRNP AB) is a member of the heterogeneous nuclear ribonucleoprotein family, which serves important functions in gene expression and signal transduction. However, the expression and clinicopathological significance of hnRNP AB in colorectal cancer (CRC) remain to be elucidated. To investigate the expression and clinical significance of hnRNP AB in CRC, hnRNP AB expression levels were analysed in two independent cohorts of patients with CRC. The results of reverse transcription-quantitative PCR, immunohistochemistry and western blot analysis demonstrated that hnRNP AB was upregulated in CRC tissues compared with the corresponding adjacent normal tissues. Immunohistochemical analyses indicated that a high expression of hnRNP AB was significantly associated with preoperative carcinoembryonic antigen (CEA; P<0.001) and carbohydrate antigen 19-9 (P=0.014) levels, tumour size (P=0.022) and infiltration (P=0.026), lymph node metastasis (P<0.001) and Tumour-Node-Metastasis stage (P<0.001). Univariate and multivariate Cox survival analyses revealed that hnRNP AB expression and preoperative CEA levels were significant independent factors affecting overall survival in patients with CRC (P<0.05). According to the Kaplan-Meier model, patients with CRC with high hnRNP AB expression exhibited significantly poorer prognosis compared with those with low hnRNP AB expression (P<0.001). In conclusion, the results of the present study demonstrated that hnRNP AB expression may serve an important role in the progression of CRC and that hnRNP AB may be considered a predictor of prognosis for patients with CRC.

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Hnrnpab regulates neural cell motility through transcription of Eps8

Cited by 10 publications

References 100 publications

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Translating neural stem cells to neurons in the mammalian brain

High hnRNP AB expression is associated with poor prognosis in patients with colorectal cancer

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